Metabolic-secretory decoupling defines a disease-intrinsic state in rheumatoid arthritis monocytes
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Objectives
Circulating monocytes from rheumatoid arthritis (RA) patients are pre-primed for inflammatory activation, but their disease-intrinsic features have not been systematically characterized. Given the important role of metabolism in shaping immune cell function, we aimed to determine how this pre-primed state is underpinned metabolically and whether these changes persist across different activation states, using an unbiased multi-omics approach.
Methods
Peripheral blood CD14⁺ monocytes from RA patients and matched healthy donors were analyzed in an undifferentiated state (M0) and after differentiation into classically activated M(IFNγ+LPS) and alternatively activated M(IL-4) macrophages, followed by acute lipopolysaccharide (LPS) stimulation. Metabolomic (untargeted LC–MS/MS), transcriptomic (RNA-seq), and proteomic (label-free mass LC-MS/MS) profiling were performed. Data was comprehensively analyzed by weighted gene correlation network analysis, differential analysis, gene set enrichment analysis, multi-omics factor analysis and metabolic flux modeling.
Results
RA monocytes exhibited a stable disease-driven signature across activation states. Integration of metabolomic, transcriptomic and proteomic data revealed an unexpected convergence on metabolic–secretory coupling, with depletion of nucleotide and redox metabolites, downregulation of mitochondrial and translational pathways, and remodeling of the secretory apparatus, including loss of cis-Golgi components. Consistently, metabolic modeling predicted reduced glycosylation fluxes, connecting metabolic changes to altered secretory capacity.
Conclusions
RA monocytes adopt a stable, disease-intrinsic state that persists across activation conditions. Multi-omics data identify a linked metabolic and secretory defect, with reduced glycosylation capacity as a potential functional consequence. This metabolic-secretory coupling represents a defining feature of RA monocyte dysfunction and a potential therapeutic target.
